An Efficient Synthesis of Β-Enaminoketone/Ester Under Grinding Condition Using Calcium Bromide As Solid Support Catalyst

Available online at www.derpharmachemica.com ISSN 0975-413XCODEN Der Pharma Chemica, 2017, 9(8):55-58 (USA): PCHHAX (http://www.derpharmachemica.com/archive.html) An Efficient Synthesis of β-Enaminoketone/Ester Under Grinding Condition Using Calcium Bromide as Solid Support Catalyst Pramod Kulkarni*, Ajay Jadhav Department of Chemistry, Hutatma Rajguru Mahavidyalaya, Rajgurunagar, Pune, Maharashtra, 410505, India ABSTRACT Calcium bromide was used as a catalyst in the synthesis of β-enaminoketone/ester from 1,3-dicarbonyl compound and amines. The reaction was carried out in mortar and pestle at room temperature. The process is mild, efficient, eco-friendly and cost-effective with the use of very small amount of catalyst; avoiding use solvent, simple product separation, and high yield. We compare this grinding reaction condition with reaction in solvent and we got better results with the grinding reaction condition. Keywords: Calcium bromide, β-Enaminoketone, Solvent free, Grindstone Chemistry, Green synthesis INTRODUCTION Solid-state chemistry has been developed rapidly as a competent and selective method, since molecules in the crystals have been arranged tightly and regularly. One of the methods belonging to this etiquette is a simple grinding method called a grindstone (mechanochemical) method which reactants are ground simply by mortar and pestle. Grinding is attracting many organic chemists due to it is performed in the absence of solvent, leading to safe and environmentally friendly synthesis. In addition to this, the proposed technique does not require external heating, leading to energy efficient synthesis and may be regarded as more cost-effective and ecologically favourable procedure in chemistry. Mechanical-induced breaking of molecular bonds, reduction of particle size, increase in surface area, formation of defects and local melting occur due to the kinetic energy supplied during grinding in solvent-free organic reactions based on grinding. The conveyance of very low measures of energy through friction in this operation leads to more efficient mixing and close contact between the starting materials on a molecular scale [1]. β-enaminones and β-enamino esters have been widely used as crucial intermediates in organic synthesis due to its variable nature as electrophiles and nucleophiles [2]. Enaminones are widely used as versatile building blocks for synthesis of important bioactive heterocyclic compounds and different biological active compounds [3]. Due to the broad range of pharmaceutical activity and key intermediate in organic synthesis create great interest of organic chemist to synthesize this molecule. The well-known route for the synthesis of β-enamino ketones and esters involves the direct condensation of β-dicarbonyl compounds with amines under reflux in an aromatic solvent with azeotropic removal of water [4]. A variety of catalysts such as metal salts [5-8], metal triflate [9-12], solid supported reagent [13-16], metal oxide [17,18], Bi(TFA)3 [8], β- cyclodextrin in water [19], VO(acac)2 [20], Ceric ammonium nitrate [21], [(PPh3)AuCl]/AgOTf [22], Ionic liquid promoted [23], Zn(ClO4)2.6H2O [24], trimethylsilyl trifluoromethane sulphonate (TMSTf) [25], Tris(Hydrogensulfato)Boron or trichloroacetic acid [26], Microwave assisted [27], Microwave radiation/K-10 [28], Phosphomolybdic acid (PMA) [29], K-10/Ultrasound [30], formic acid [31]. However, some of these methods have synthetic shortcomings such as use of expensive or combinations of catalysts, use of toxic solvent, longer reaction times, use of excess amount of catalyst, low yield, tedious work-up procedures, lack of selectivity, in some cases catalyst preparation requires, use of toxic metal catalysts. Therefore, there is scope to develop a new and efficient method for synthesis of β-enamination of 1,3- dicarbonyl compounds. Calcium bromide is obtained by the interaction of bromine and milk of the lime in the presence of ammonia. It is readily soluble in water and absolute ethanol [32]. It is thermally and chemically stable. Use of calcium bromide in organic synthesis is very rare [33,34]. Herein, we report the use of calcium bromide as a catalyst for the synthesis of β-enaminoketone/ester under solvent free condition. EXPERIMENTAL SECTION General All chemicals were purchased from Loba chemicals, Merck, Sigma Aldrich and used without further purification. Commercially available Calcium bromide is used as a catalyst and it is purchased from Loba chemicals. Melting points were determined by open capillary method and are uncorrected. All products are known and their structure is confirmed by Infra-red (IR), Proton Nuclear Magnetic Resonance (1HNMR), Carbon-13 Nuclear Magnetic Resonance (13CNMR), High Resolution Mass Spectrometry (HRMS) and comparison of this spectral data with those reported in the literature. Progress of the reaction was monitored by Thin Layer Chromatography (TLC) on precoated silica gel 60 F254 sheets. 55 Der Pharma Chemica, 2017, 9(8):55-58 Pramod Kulkarni et al. General experimental procedures for synthesis of β-enaminones Method A: In a mortar and pestle, equimolar amounts of primary amines (1 mmol) and β-dicarbonyl compound (1 mmol) along with calcium bromide (2 mol%, 0.02 mmol, and 0.0047 g) as a catalyst were placed. The reaction mixture was continuously grinded for the specified time as given in Tables 1 and 2. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and product was extracted with ethyl acetate (2 × 15 ml) and washed with water and brine solution. The combined organic phases were dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography on silica gel using ethyl acetate-petroleum ether (2:8 v/v). All products are known and their structure is confirmed by IR, 1HNMR, 13CNMR and HRMS. Table 1: Synthesis of β-enaminoketones and β-enamino esters using calcium bromide under solvent free grinding conditiona Time (min) (%) Yieldb Entry β-dicarbonyl compounds Amines Product (3) M.P. [Ref] Under grinding In solvent Under grinding In solvent 1 Acetylacetone Aniline 3a 25 120 97 89 45-47 [17] 2 Acetylacetone 4-methylaniline 3b 22 90 92 83 66-68 [16] 3 Acetylacetone 4-chloroaniline 3c 27 85 90 81 61-62 [16] 4 Acetylacetone 4-nitro aniline 3d 55 300 87 78 141-143 [17] 5 Acetylacetone 4-methoxyaniline 3e 30 74 94 83 45-46 [16] 6 Acetylacetone o-nitroaniline 3f 120 360 No reaction No reaction - 7 Acetylacetone 2-methyl aniline 3g 65 240 74 57 38-40 [4] 8 Acetylacetone 2-methoxyaniline 3h 75 280 58 47 Oil [18] 9 Acetylacetone methyl amine 3i 20 82 84 74 46-48 [23] 10 Acetylacetone butyl amine 3j 25 78 87 78 Oil [16] 11 Ethyl acetoacetate Aniline 3k 30 105 92 82 Oil [16] 12 Ethyl acetoacetate 4-methyl aniline 3l 24 94 88 81 Oil [16] 13 Ethyl acetoacetate 4-methoxy aniline 3m 20 68 90 80 47-48 [16] 14 Ethyl acetoacetate 4-chloro aniline 3n 38 130 83 73 56-58 [16] 15 Ethyl acetoacetate 4-bromo aniline 3o 45 170 81 72 53-56 [18] 16 Ethyl acetoacetate 1-naphthylamine 3p 55 200 74 61 Oil [18] 17 Ethyl acetoacetate benzyl amine 3q 50 240 78 70 Oil [26] 18 Ethyl acetoacetate 2-methyl aniline 3r 67 265 58 50 Oil [4] 19 Ethyl acetoacetate butyl amine 3s 30 110 73 59 Oil [22] 20 Ethyl acetoacetate 2-nitro aniline 3t 120 360 No reaction No reaction - 21 1-phenylbutane-1,3-dione Aniline 3u 75 210 78 71 107-109 [31] 22 1-phenylbutane-1,3-dione 4-methoxy aniline 3v 50 240 81 74 92-95 [31] 23 1-phenylbutane-1,3-dione 4-methyl aniline 3w 54 200 85 77 86-87 [31] 24 1-phenylbutane-1,3-dione 4-chloroaniline 3x 63 260 82 74 127-129 [31] a: Reaction conditions: Method A in mortar and pestle and Method B with stirring in Ethanol amine (1 mmol) and β-dicarbonyl compound (1 mmol) and calcium bromide (2 mol %, 0.0 2 mmol) were placed b: isolated yield Method B: To a mixture of β-dicarbonyl compound (1 mmol) and primary amines (1 mmol) in ethanol (5 ml), calcium bromide (2 mol%, 0.02 mmol, 0.0047 g) was added at room temperature with stirring. The reaction mixture was stirred for the specified time as given in Tables 1 and 2. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with water and product was extracted with ethyl acetate (2 × 15 ml) and washed with water and brine solution. The combined organic phases were dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography on silica gel using ethyl acetate- petroleum ether (2:8 v/v). Table 2: Synthesis of cyclic β-enaminoes using calcium bromide under solvent free grinding conditiona Time (Min) % Yieldb β-dicarbonyl Entry Amines Product (4) Under M. P.[Ref] compounds Under grinding In solvent In solvent grinding 1 Dimedone aniline 4a 45 125 92 86 185-186 [16] 2 Dimedone 4-chloroaniline 4b 53 160 86 80 192-194 [26] 3 Dimedone 4-bromoaniline 4c 60 194 82 79 220-221 [16] 4 Dimedone 4-methoxy aniline 4d 40 135 91 85 193-195 [16] 5 Dimedone 4-nitroaniline 4e 75 250 78 70 192-193 [26] 6 Dimedone 2-methoxy aniline 4f 85 300 63 57 125-127 [16] 7 Dimedone 3-nitro aniline 4g 70 256 82 76 168-170 [26] 8 Dimedone 2-nitroaniline 4h 120 360 No reaction No reaction - 9 Dimedone benzyl amine 4i 65 175 77 73 127-128 [16] 10 Dimedone butyl amine 4j 65 182 86 79 117-119 [16] a: Reaction conditions: Method A in mortar and pestle and Method B with stirring in Ethanol amine(1 mmol) and β-dicarbonyl compound (1 mmol) and calcium bromide (2 mol%, 0.02 mmol) were placed b: isolated yield RESULTS AND DISCUSSION The condensation of aniline and acetyl acetone was selected as a model reaction.

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